Bis-carboxyethyl germanium sesquioxide and process for preparing same

ABSTRACT

The compound bis-carboxyethyl germanium sesquioxide is prepared as illustrated by the following equations:

United States Patent Asai et al.

[ Sept. 5, 1972 [72] Inventors: Kazuhiko Asai, Tokyo-to; Kazuo Makabe, Kamakura-shi, both of Japan [73] Assignee: Daiichi Yakuhin Sangyo Kabushiki Kaisha, Tokyo-to, Japan [22] Filed: March 7, 1969 [21] Appl. No.: 805,370

[30] Foreign Application Priority Data March 29, 1968 Japan ..43/200s5 [52] US. Cl. ..260/429 R, 424/287 [51] Int. Cl. ..C07j 7/00, A6lk 27/00 [58] Field of Search ..260/429 [56] References Cited OTHER PUBLICATIONS Lesbre et al. Compt. Rend. Vol. 247 (1958) p. 471- Primary Examiner-Delbert E. Gantz Assistant ExaminerA. P. Dem'ers Attorney-Scrivener, Parker, Scrivener and Clarke ABSTRACT The compound bis-carboxyethyl germanium sesquioxide is prepared as illustrated by the following equations:

GeIIClg CIIgzCHCN Cl Gn-Cll Cll' CN Hydrolysis Cl3Ge-CII2CIIzCN ChGeCIhCIhCOOlI Hydrolysis 2C1; GeCHzCHzC 0 C1 This compound is effective for inhibiting the proliferation of Ehrlich ascites tumor cells.

2 Claims, No Drawings BIS-CARBOXYETI'IYL GERMANIUM SESQUIOXIDE AND PROCESS FOR PREPARING SAME DETAILED EXPLANATION OF THE INVENTION This invention relates to the compound bis-carboxyethyl germanium sesquioxide and having the following formula:

This is a compound and the invention also relates to a process of preparing it.

The compound of the invention inhibits the proliferation of Ehrlich ascites tumor cells.

It is believed that the mechanism by which the compound of the invention operates, is derived from the fact, already known, that the electric potential of abnormal cells in the living body is different from thatof normal cells.

Germanium, which has the atomic number of 32, is an atom having 32 electrons. Four of these electrons are located in an outer orbit and are unstable, being capable of separation from the rest under certain conditions. This property of germanium is utilized for transistors or diode rectifiers, as is popularly known. And there is a phenomenon that, when one of these four electrons has escaped, there results what is referred to as a positive hole of electric potential, to which other nearby electrons are drawn in. The composition of germanium being so, its organic compound is apt to cause electric charge transfer and to generate organic free radicals.

Applicants have for a long time studied the components of plant substances used for the so-called Chinese medical herbs, which have been known to be effective to check abnormal cells in the living body, and discovered that they contained a very large content of germanium, for example, 320 ppm in ginseng, 257 ppm in water-caltrop nut, 124 ppm in box-thorn nut, 108 ppm in wisteriaknot, 50 ppm in pearlbarley seed, 58 ppm in erythrorhizon, 76 ppm in comfry, and 756 ppm in garlic. This fact appears to indicate that germanium exists within these plants in the form of organic compounds.

The presence of this property of germanium and its peculiar characteristics previously described, led applicant to conclude that, if an organic germanium compound could be found that has the property to absorb a nearby electron, due to the escape of an electron resulting in a positive hole of electric potential, it could be utilized to change the electric potential of abnormal cells in the living body and to check their proliferation, it being known that the electric potential of abnormal cells is different from that of normal cells. Extensive research on the activities of various germanium compounds then followed. As a result, it was discovered that this activity is displayed by the compound of the invention, and this discovery led to the invention.

The process of making the compound according to the invention is as follows: B-cyanoethyltrichlorogermanium trichlorogermanium ethylene cyanide) is obtained by the action of acrylonitrile on the known compound trichlorogermanium (germaniumchloroform). B-Cyanoethyltrichlorogermanium is converted into B- trichlorogermanium propionic acid (trichlorogermanium propionic acid) by hydrolysis in the presence of a mineral acid and by the action of thionylchloride, this latter compound is converted to trichlorogermanium propionyl chloride. Hydrolysis of this compound with water produces bis-carboxylethyl germanium sesquioxide.

The described-process is illustrated by the following equations:

ChGOCHzCHgCOOH SOC]: Cl GeCH CHgCOOH O=GeCH2CHgCOOH Hydrol sis 2Cl GeCII CHgCOCl -r Bis-carboxyethyl germanium sesquioxide and, so produced, was tested on mice to which Ehrlich ascites tumor has been transplanted.

Test mice: DD Shizuoka, 4 weeks old.

Test procedure:

2,200,000 cells of Ehrlich ascites tumor, as the abnormal cells, were transplanted into the abdomen of mice. After 24 hours, 1 ml. of a sterile aqueous solution of 20 mcg of the compound of the present invention was injected into the abdomens of seven mice and a control into the abdomens of five of the mice. The injection was made every day for 7 days, and on the 8th day, dissection was conducted.

Examining the results, it is seen that the administered group were very vigorous and had good appetite compared with the control group, showing no external appearance of reaction, the control group showed stagnant ascites whereas the administered group showed neither ascites stagnation nor bleeding, the proportion of the number of tumor cells in the bodies of the administered group was approximately 26 percent against percent in the bodies of the control group, and that there was a good indication of the effective checking of fissiparism.

The compound, bis-carboxyethyl germanium sesquioxide is a, are white, crystalline powder, and capable of polymerization on heating. Its melting point is impossible to measure, since heating to a higher temperature causes decomposition. In water solution, the oxygen in germanium sesquioxide is hydrated and the hydrogen stimulates charge transfer, thus causing activation. 7

The novel compound according to the present invention is of a very low order of toxicity. The LD in mice as determined by hypodermic injection is 3,5g/kg of body weight.

The compound of the invention is soluble in water, and therefore it is most convenient to formulate it as solutions in sterile, pyrogen-free water, although any pharmaceutically acceptable carrier may be used.

A preferred therapeutic composition of the invention will comprise an aqueous solution containing from 0.01 to 0.4 by weight of the active ingredient.

Compositions containing the compound according to the invention can be administered orally or Number of E.A.'I. Ascites amount, Aver- '1.I.,

Total age percent Summary TABLE Weight Just be- Third Sixth fore dising day day section ml. Unit Mouse Startnumber X X L are 1 +1.). 1. 1 +L+1+++ i 1111 +0 dfiadfi n n i zuu ..(,.l .(E.( g nnmwdfi 3 0M .123 1 1111 3. .11.). 110%. ++d+ d (.m dd wsdd m M m W+ mi w a w ++H+ eeh++ d md d+ d+ no 2+ H H e 1 e T T n P m d Ham WDH @(G 0.0%WH 11. 1 H .20.. 11111 ++M mmTTmTr +r+r r immim m ++TTT \J A11 A v e s s 1 1 a n 111 001 12 .1 .1111 fiififii fiafia H 11 h 1 1. 1 1 1 0 w EEEEEEE E(E(E W(EE(EE( ((EEE wwwwwww .1. m 1 ..1..1..1..1,.1:1.1. L nmr ur nrnnr 1 1 1 SSSSSSS AA WW m m n 1 1 .SSQ WWWWW V W WW 1.111.111 11 1 1. m m mwfinmw mm mmmm mwmmwmm Mmwmm H 0 S [l 1 P wi ll a m a 1 m m a e m 2 m 1% a a W L 1 W W 2 4 m 3 9 H 1 w M 7 m 7 E 1. d a E W i w m i w a 2 4 e w 4 3 4 0 7. W W 1 2 W M To" m 7 4 00 0 0 V 4 8 1 21 wwww wm wmmmmmw m mm i w w w m 72 6 7 1 1 5 :1. e i i i ii. 1 4528 2 E l 4 25 no" H W W M O m 0m00000 OTW O W 00000 w +w w w 2 0 W 4 W mm%m% 80m5006 9 8722 47 .m 1 .M H .m U WM m 435-WvH6J0 m m m n o i 1 X M m N t 6818722 4877880 0057808 71471 .11 .1 1. w u m .m 11 1 1102100 1 5 0 1 3 m o. w e E u m m H w m m T 5005373 50550? 20520 e m m 11 2100 11121 01 001 2110 L5 0 L3 0 S0 0.0.00.0.00 20551 W m 5 Am 1 11001 ++01+ 1 h m a 1 e .10. W S. 9 7++ I t 12 1 1 :1 v 50 0 S "4 g +1 0 1 r m n Mum 0 505 0 5002545 3355403 551 m 0 23 2 1 w m mwm 1 110 2 +1+ ++&++ ++0 1+ 12 1 2 m m w m m 1 0 0 ++0 0 o 5 0 +o 5 0 5 5 0 ++0 H and .1... w m .5. 30.23 0 1 3 2% 2 1 12 22 0 3 0 S r 2 0Rwflw0m w9 4 m a m 2212111 2% n m 2 m 0 0 90 0 0 5 H r M h 0 3 50126 55 04550 du fl 22121 w o d .1 ma 1 2u122o ++L+++ L21o 1 +d+a 2 2 2 m m m n h s n++ 5 1 0 20 0 ;m0 a 0 +5 0 00500 00655 m M m m 0 010 0 5 ammaminwii 0 5 0 2190.002 0 c 2212122 t W W mmm H 1 m 1 I a 1 0b dv. 0500500 0 05505 0505500 00555 505500 I m lo( ha 1 Lnwowowomomm MMM MN M u mm d flmwwwwfl WEED mm mflmflflmm mmmmwm 221111 mN m e m T 150. N ww m 505 50 5000500 5050505 50550 1234507 23456 5 O LO-9990 22222 W Fr. 221111 9 mmmmwmwm wmw2mmfl N m t n hfl .1 L m 12345 6 89 i ll m mflm mr 67 m REM w flllmm H%M%% m km U0 MW =Ec N lill u il i i Y S v 1 X H e T .T 1 m mm w h H r ix m L MA o m l av n.m r M H m "w ma T 1b] t Bem 0 lmmmw m B C Kdnu A B C 0 One millilitre of physiological salt water.

Example l: To 18 gr. of germaniumchloroform are added 6 gr. of acrylonitrile, and by heating under an atmosphere of 55 nitrogengas, Byanoethyltrichlorogermanium is obtained. This is converted to B-trichlorogermanium propionic acid by adding hydrochloric acid solution and heating. This is converted through reaction upon the dropwise addition of 12 gr. of thionylchloride, to trichlorogermanium propionyl chloride, which is recovered by distillation in vacuo. After complete hydrolysis takes place with water, bis-carboxyethyl germanium sesquioxide is obtained. This is washed with water until chlorine reaction disappears and a white powder is obtained. The yield is about 6 gr. Anal. calcd. for C,l-l ,O,(I1E Calculated value: 1 H2294, Ge:42.64 Found 113.00, Ge:42.41

Notes.-Deg.=Degeneration degree; PSW 1= It has been observed that chemical reaction involving the compounds of the invention occurin the body only The following examples will serve to illustrate the preparation of the compounds of the present invention but are not to be construed as limiting in nature.

parenterally by intramuscular or intravenous injection. Also, if the diseased area is defined by a body cavity, the aqueous solution can be applied directly to the diseased area as by a catheter or irrigation. If administration is to be by the oral route, the carrier can be a solid and in the form of a powder or tablet. The solid carrier can be any of those commonly used in making medicinal formulations.

at the site of abnormal cells, and this is believed to give credence to the theory set forth above.

What is claimed is: i l. Bis-carboxyethyl germanium sesquioxide, of the formula O=GcCllzCllgC0Oll O=( eOH:CII2COOH 2. A process of producing bis-carboxyethyl germanium sesquioxide, comprising reacting germaniumchloroform with acrylonitrile to produce B- 

2. A process of producing bis-carboxyethyl germanium sesquioxide, comprising reacting germaniumchloroform with acrylonitrile to produce B-cyanoethyltrichlorogermanium; hydrolyzing B--cyanoethyltrichlorogermanium in the presence of a mineral acid to produce B-trichlorogermanium propionic acid; reacting B-trichlorogermanium propionic acid with thionyl chloride to produce trichlorogermanium propionyl chloride; and hydrolyzing trichlorogermanium propionyl chloride to obtain bis-carboxyethyl germanium sesquioxide. 